In the field of implantable devices, such as stents, cardiac valves, cardiac assist devices, reconstructive joint replacement implants, spinal implants, vascular prostheses etc., a critical point is the material employed to manufacture or coat the above mentioned devices. These materials have to be as biocompatible as possible in order to avoid adverse reactions (inflammation, hypersensitivity, foreign-body response, etc.),
The devices are made of different kind of materials. Some of them are made of metallic alloys. Others are made of polymeric materials, including polyesters, polyethers, polyamides, silicone polymers, polyethylenes, polyfluoroethylenes, polyurethanes or polyacrylics, among others.
When the devices rest in the body for a long period of time, adverse reactions can be raised, such as acute or chronic inflammation. The adverse reactions are due to the initial damage made by the device, or due to the lack of biocompatibility of the material or of its degradation products. In implantable devices that are designed to be biostable it is possible that in a large period of time a little degradation could start due to deficient mechanical properties of the implant material or for another reason. In this case the degradation products probably would initiate an inflammation and a foreign body response. This biological response against the material leads to the degradation of the material; liberating fragments that may be toxic or may increase the biologic reaction against the material. The degradation would accelerate due to this biological response and could initiate a vicious circle that would generate the failure of the device or another medical issue for the patient. Finally, this process culminates with the failure of the medical device.
In other medical applications, such as in dental or bone regeneration, self-curing formulations based on acrylic polymers are used. These formulations include Eugenol-derived monomers chemically anchored to the polymeric structure and conserve the analgesic and antiseptic properties of the Eugenol. The Eugenol-derived monomers are disclosed in the patent application WO 2007/93662. These monomers are employed as a component of the liquid phase of self-curing formulations for dental implants. However, the use of the acrylic polymers in the field of manufacture of medical devices is limited due to the inherent difficulty to modulate their mechanical properties.
Other medical devices are conceived to be absorbed by the tissues to finally release an active ingredient. For this purpose some patches or implantable devices are made of polymers including drugs as monomers. One example of this is set in the patent document EP 1032605 B1, wherein in a polyanhydride-based polymer a drug-derived monomer is linked to the polymer skeleton through labile bonds. The object of the polyanhydrides disclosed in EP 1032605 B1 is that the drug-derived monomer is released to deliver the drug. This type of polymers are useful for medical devices which have to rest in the body for short periods of time, since the device is finally disintegrated and, for example, they are not suitable for the construction of cardiac valves. The polyanhydride has a disadvantage similar to the polyacrylic polymers, the range of their mechanical properties is narrow and difficult to modulate.
Examples of polymeric constructions with the aim of finally releasing a therapeutic or diagnostic agent to a preferred organ or target are widely disclosed in the document by Haag et al., “Polymer Therapeutics: Concepts and Applications”, Anqewandte Chemie, 2006, vol. 45, pp. 1198-1215. This document is a review showing polymer-protein conjugates, drug-polymer conjugates, as well as supramolecular drug-delivery systems. The drug or the protein of the conjugates is linked with the polymeric structure as an appended compound.
A further example is WO 2010/040188 which discloses a biodegradable polymer comprising releasable bioactive moieties being pendant from and covalently bonded to the polymer backbone, wherein the biodegradable polymer backbone is formed from monomeric units that are each coupled via a biodegradable moiety, and wherein the bioactive moieties are capable of being released at rate equal or faster than the rate of biodegradation of the polymer backbone. The polymers of the present invention on the contrary are biostable and present the drugs either as part of the polymer backbone or as terminal monomer units. The polymers disclosed in WO 2010/040188 can be used in the preparation of an implantable scaffold, stent or biomedical coating or dressing or adhesive. In addition WO 2010/040188 discloses monomer-bioactive moiety conjugates suitable in preparing biodegradable polymers comprising a drug and presenting two terminal functional groups capable of undergoing polymerization, as well as some intermediate compounds useful for the synthesis of monomer-bioactive moiety conjugates which are different from the monomer compounds of the present invention.
Also WO 02/098477 discloses bioactive fluoroalkyl surface modifiers (polymers) containing biologically active molecules, such as pharmaceuticals, for use in admixture with a base polymer for coating or forming medical devices. The bioactive fluoroalkyl surface modifiers disclosed in WO 02/098477 differ from the polymers of the present invention in that the biologically active molecules grafted to the so called linkB segment within the bioactive fluoroalkyl surface modifier are pendent, and directly and covalently linked without any spacer.
US2010/0041748 discloses fatty acid acetylated salicylate derivatives, fatty acid acetylated diflunisal derivatives and fatty acid acetylated triflusal derivatives, a process for their synthesis and its use for the treatment or prevention of inflammatory disorders. US2010/0041748 discloses as well intermediates compounds involved in the synthesis of the mentioned derivatives which present a similar but different structure from the monomer compounds of the present invention, differing at least in the type of bond linking the drug to the spacer.
EP 1710257 discloses hyaluronic acid derivatives in which an anti-inflammatory drug is bound to hyaluronic acid through a covalent bond via a spacer having a biodegradable region, and a production process thereof, in which a spacer is introduced into a drug in advance and thereafter the resulting product into hyaluronic acid. The intermediate compounds involved in said process and disclosed in EP 1710257 are however different from the monomer compounds of the present invention, and differ at least in the type of bond linking the drug to the spacer.
U.S. Pat. No. 4,179,337 discloses peptides and polypeptides coupled to polymers which posses a substantially linear ethereal or carbon carbon backbone, for instance polyethylenglycol and polypropylenglycol, which are substantially non-immunogenic and retain a substantial proportion of the desired physiological activity of the peptide or polypeptide. Some of the disclosed compounds have a similar but different structure from the monomer compounds of the present invention, and differ either in the type of bond linking the drug to the spacer and/or in the type of drug being different from a peptide or polypeptide.
US 2003/0220468 discloses derivatives of nonsteroidal anti-inflammatory agent which provide the therapeutic effect of the drug while causing a much lower incidence of the common side-effects. Some of the derivatives present a similar structure to the monomer compounds of the present invention, but are however different, differing at least in the type of bond linking the drug to the spacer.
U.S. Pat. No. 5,589,563 relates to surface-active endgroups (SMEs) containing polymers in which the endgroups contain covalently bonded surface active groups such that the surface activity of said polymers is controlled by said surface active groups. The SMEs groups improve the biostability of the polymers, such as polyurethanes or polyurethaneureas, which can be formed into articles to be implanted in humans or animals. Preferred SMEs are monofunctional polyethylenoxide-amines, monofunctional polyethylenoxide-alcohols, polydimethylsiloxane-amines and dodecylamines.
In the PCT application WO 2005/39489 some polymers useful to locally administer anti-inflammatory substances are disclosed. These polymers comprise anti-inflammatory substances embedded into the backbone of the same. The substances are finally released into the body to attain their effect. The document presents a wide range of putative linkages between the anti-inflammatory substances and the backbone of the polymer, and it indicates also that the release of the anti-inflammatory substances is done in a period of at least about 2 hours to about years, stating that the degradation properties may be controlled by modifying the specific linkage between the anti-inflammatory substances and the backbone of the polymer. Nonetheless, the document only shows combinations of breakable linkages leading to hydrolysis of the compounds from 8 hours to 2 months.
Thus, compounds that allow minimizing the adverse reactions of medical devices in the body are needed. In particular, there is a need of compounds that can be used for the manufacture of medical devices with the aim of resting for a long time in the body while avoiding the adverse reactions occasioned by the implant to the organism. Another property that is very important for these materials is that their mechanical properties have to fit exactly to the wanted application; otherwise the material will degrade with time.